Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas
Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas
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DOI：
10.1007/s00109-005-0706-9
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发表时间：
2006-01-01
影响因子：
4.7
通讯作者：
Honjo, T
中科院分区：
文献类型：
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作者：
Yamamoto, N;Tanigaki, K;Honjo, T
哺乳动物耳蜗内的内耳毛细胞在出生后被认为是不能再生的，这阻碍了主要由毛细胞损失引起的感音神经性听力障碍的治疗。耳蜗的感觉上皮由毛细胞和支持细胞组成，它们都起源于共同的前体细胞。Notch/RBP-J信号通路是一条进化上保守的信号通路，参与发育阶段甚至出生后哺乳动物器官中各种细胞类型的特化。在胚胎内耳中，Notch/RBP-J信号抑制来自祖细胞的毛细胞命运的特化。然而，其在出生后内耳中的功能尚不清楚。我们发现，抑制Notch/RBP-J信号，无论是有条件的中断Rbpsuh基因或治疗与γ-分泌酶抑制剂，可以引起异位毛细胞的支持细胞区域的器官Corti从新生小鼠耳蜗毛细胞出生后没有被认为是再生。我们还发现Hes 5的下调和Math 1的上调与异位毛细胞诱导相关。这些结果表明，Notch/RBP-J信号抑制支持细胞分化成毛细胞，即使在出生后的日子，这意味着Notch/RBP-J信号的抑制剂可以用来帮助再生毛细胞出生后，从而为潜在的治疗毛细胞损失引起的顽固性感音神经性听力障碍没有遗传操作。
Mammalian inner ear hair cells in cochleas are believed to be incapable of regeneration after birth, which hampers treatment of sensorineural hearing impairment mainly caused by hair cell loss. Sensory epithelia of cochleas are composed of hair cells and supporting cells, both of which originate from common progenitors. Notch/RBP-J signaling is an evolutionally conserved pathway involved in specification of various cell types in developmental stage and even in some of postnatal mammalian organs. The specification of hair cell fate from the progenitors is inhibited by Notch/RBP-J signaling in embryonic inner ears. However, its function in postnatal inner ears is unknown. We showed that inhibition of Notch/RBP-J signaling, by either conditional disruption of the Rbpsuh gene or treatment with a gamma-secretase inhibitor, could give rise to ectopic hair cells in the supporting cell region in organs of Corti from neonatal mouse cochleas where hair cells have not been considered to regenerate after birth. We also showed that down-regulation of Hes5 and up-regulation of Math1 were associated with ectopic hair cell induction. These results suggest that Notch/RBP-J signaling inhibits supporting cells from differentiation into hair cells even in postnatal days, implying that inhibitors of Notch/RBP-J signaling can be used to help regenerating hair cells after birth and thus serve for potential treatment of intractable sensorineural hearing impairment caused by hair cell loss without genetical manipulation.